In the first of two matches between the teams in the space of seven days, they will both be looking to lay down an early marker in their bid to progress to the quarter-finals.
Match preview
Colo-Colo suffered a costly 4-3 defeat against Fortaleza in their final Copa Libertadores group-stage fixture on May 25, which sent them packing into the second tier of South American continental football.
Daniel Moron's men headed into the clash needing just a point to make it through to the next round, but a Yago Pikachu strike just past the hour mark proved to be the decider in a seven-goal thriller.
Los Albos are unbeaten in their subsequent three domestic outings and sit top of the Primera Division, while they have also reached the last eight of the Chilean Cup.
The Santiago-based club now set out to begin their quest for a first-ever Copa Sudamericana title, with their closest attempt to going all the way coming back in 2006 when they reached the final.
Having kept clean sheets in three of their last four home matches, Wednesday's hosts will be looking to maintain their defensive solidity en route to a positive result.
Internacional were too strong for Nueve de Octubre in their final Copa Sudamericana Group E involvement on May 25, which ended 5-1 at the Estadio Beira-Rio.
Rodrigo Dourado was the star of the show as he grabbed a superb hat-trick to lead Mano Menezes's men to an emphatic win in Porto Alegre.
Clube do Povo are unbeaten in six of their seven league matches since then and currently sit fourth in the Brasileiro at the moment.
Unbeaten in their last eight away games across all competitions, Wednesday's visitors set out to take control of the tie ahead of next week's return leg.
Colo-Colo form (all competitions):
Internacional Copa Sudamericana form:
Internacional form (all competitions):
Team News
Twenty-year-old Jeyson Rojas is suspended for the game courtesy of his sending off in Colo-Colo's last Copa Libertadores outing.
Off the back of a three-goal haul in his most recent appearance, Juan-Martin Lucero will head into this one with the wind in his sails.
Gabriel Mercado served a one-game ban in Internacional's 3-0 thrashing of Coritiba on Saturday, but the defender is eligible to feature on Wednesday.
Federico Bustos is a doubt for the away side after the Argentine was hauled off with an injury in the first half of the aforementioned game.
Colo-Colo possible starting lineup:
Carabali; Falcon, Zaldivia, Opazo, Gutierrez; Pavez, Fuentes; Solari, Gil, Zavala; Lucero
Internacional possible starting lineup:
De Sousa; Heitor, Vitao, Mercado, Lara; Edenilson, De Pena, Gabriel; Taison, Alemao, Henrique